Pirfenidone Treatment Attenuates Fibrosis in ADPKD

Background: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease marked by progressive cyst formation, inflammation, and fibrosis of the kidneys. Renal fibrosis involves excessive extracellular matrix (ECM) deposition and reduced matrix degradation, leading to scarring and decline in kidney function. Myofibroblasts, the key producers of ECM, play a central role in this process. Our previous research demonstrated that peri-cystic myofibroblasts contribute significantly to fibrosis and cyst growth in ADPKD, and their depletion reduced fibrosis and slowed cyst growth. Given the lack of effective anti-fibrotic therapies for ADPKD, this study determines the potential of Pirfenidone to inhibit fibrosis in ADPKD and elucidates its underlying mechanisms. Methods: The anti-fibrotic effects of Pirfenidone were evaluated in vitro, using cells isolated from human ADPKD kidneys and in vivo using Pkd1RC/RC (RC/RC) mice, an orthologous slowly progressing model of PKD. RC/RC mice received Pirfenidone or vehicle by oral gavage at a dose of 200 mg/kg body weight, administered twice daily (between 8–9 AM and 4–5 PM), from 4 to 6 months of age. In vitro studies were conducted using primary culture human ADPKD myofibroblasts and the NRK-49F rat renal fibroblast cell line. Results: Analysis of Kidney Interactive Transcriptomics (KIT) single-nucleus RNA sequencing data from human normal and ADPKD kidneys revealed that fibroblasts are the primary source of collagens, ECM proteins, ECM-degrading enzymes, and profibrotic matricellular proteins compared to other renal cell types. In RC/RC mice, two months of Pirfenidone treatment led to a significant reduction in renal fibrosis, reduced blood urea nitrogen levels and decreased cyst burden compared to vehicle-treated controls. Pirfenidone also suppressed TGFβ signaling, as indicated by reduced p-SMAD3/SMAD3 protein levels. Moreover, in vitroexperiments demonstrated that Pirfenidone reduced the expression of ECM and fibrosis-related proteins, and significantly inhibited the proliferation, differentiation, and migration of primary human ADPKD myofibroblasts. Conclusion: Our study shows that Pirfenidone effectively reduces renal fibrosis, improves kidney function, and decreases cyst burden in RC/RC mice, demonstrating that it may be a therapeutic candidate for the treatment of fibrosis in ADPKD. Funding: NIDDK Support